For recovering cocaine addicts, even the slightest reminder of their past drug use, such as people they used cocaine with, places they bought drugs, or even music they listened to while using, can trigger a relapse. Addiction researchers call this cue reactivity. Addiction researchers have also found that people who act impulsively have a greater risk of relapse.

Consuming cocaine elevates levels of the neurotransmitter serotonin. Recent studies have connected cue reactivity and impulsivity to brain circuits that involve serotonin receptor proteins that sit on neuron surfaces, says Kathryn Cunningham of the University of Texas Medical Branch.

To understand the biochemistry of relapse, Cunningham and her colleagues previously focused on two varieties of serotonin receptor, 5-HT2AR and 5-HT2CR. Drugs that block 5-HT2AR signaling or increase 5-HT2CR signaling suppress impulsivity and cocaine seeking behaviors in laboratory animals. But researchers must use high concentrations of the individual drugs to get results, which can cause unwanted side effects, Cunningham says.

Cunningham and her colleagues wondered whether two drugs, one that shuts down 5-HT2AR and another that turns on 5-HT2CR, could work together to suppress relapse in rats better than either drug alone. If so, researchers could prevent relapse by using low amounts of each drug, reducing the potential for side effects.

To test their idea, the researchers treated rats with low doses of the drugs M100907, which turns off 5-HT2AR, and WAY163909, which turns on 5-HT2CR. They then subjected the rats to behavioral tests that measure impulsivity and cue reactivity.

In the impulsivity test, a rat got a food pellet when it placed its nose in a hole in its cage, but only if a light in the hole was turned on. If the light was off when a rat placed its nose in the hole, the animal received no reward. Any time the rodents repeatedly stuck their noses in unlit holes, the scientists called it impulsive behavior. Compared to rats receiving a low dose of M100907 alone or WAY163909 alone, animals treated with doses of both drugs at the same time showed about 40% or 25% less impulsivity, respectively.

In the cue reactivity test, the scientists trained rats to self-administer cocaine by pressing a lever. When a rat pressed the lever, a light would come on and the animal would receive a small hit of cocaine through a tube inserted into its vein. As a result, the rat learned to associate the light and the sound of the pump that infused the drug with the cocaine high. After this initial training, the researchers weaned the rats off the drug by making it so that the lever didn’t turn the light on or trigger a cocaine injection. Once the rats stopped compulsively hitting the cocaine lever, the researchers then turned on the light and the pump to see if the cues would trigger the rodents to go back to the lever. In response to the cocaine cues, animals treated with both drugs hit the lever about 40% less than those treated with either drug alone, suggesting that the drug combo reduced cue reactivity.

Donna Huryn of the University of Pennsylvania says that the work “suggests a novel approach in treating cocaine addiction and opens new avenues for drug design.”

Cunningham’s team now wants to develop a compound that incorporates the structures of both M100907 and WAY163909, in the hopes of producing a more potent drug. “Because many disorders such as drug addiction, attention-deficit hyperactivity disorder, eating disorders, and obesity involve problems with impulse control, this work may have broader implications than for just cocaine addiction,” Cunningham says.